Decision Regret among Patients with Early-stage Lung Cancer Undergoing Radiation Therapy or Surgical Resection.

AIMS: Clinical equipoise exists regarding early-stage lung cancer treatment among patients as trials comparing stereotactic body radiation therapy (SBRT) and surgical resection are unavailable. Given the potential differences in treatment effectiveness and side-effects, we sought to determine the associations between treatment type, decision regret and depression. MATERIALS AND METHODS: A multicentre, prospective study of patients with stage IA-IIA non-small cell lung cancer (NSCLC) with planned treatment with SBRT or surgical resection was conducted. Decision regret and depression were measured using the Decision Regret Scale (DRS) and Patient Health Questionnaire-4 (PHQ-4) at 3, 6 and 12 months post-treatment, respectively. Mixed linear regression modelling examined associations between treatment and decision regret adjusting for patient sociodemographics. RESULTS: Among 211 study participants with early-stage lung cancer, 128 (61%) patients received SBRT and 83 (39%) received surgical resection. The mean age was 73 years (standard deviation = 8); 57% were female; 79% were White non-Hispanic. In the entire cohort at 3 months post-treatment, 72 (34%) and 57 (27%) patients had mild and severe decision regret, respectively. Among patients who received SBRT or surgery, 71% and 46% of patients experienced at least mild decision regret at 3 months, respectively. DRS scores increased at 6 months and decreased slightly at 12 months of follow-up in both groups. Higher DRS scores were associated with SBRT treatment (adjusted mean difference = 4.18, 95% confidence interval 0.82 to 7.54) and depression (adjusted mean difference = 3.49, 95% confidence interval 0.52 to 6.47). Neither patient satisfaction with their provider nor decision-making role concordance was associated with DRS scores. CONCLUSIONS: Most early-stage lung cancer patients experienced at least mild decision regret, which was associated with SBRT treatment and depression symptoms. Findings suggest patients with early-stage lung cancer may not be receiving optimal treatment decision-making support. Therefore, opportunities for improved patient-clinician communication probably exist.

Relationship-building to develop an Indigenous community-based epidemiological study investigating developmental resilience factors among children with prenatal substance exposure.

Tribal Nations experience substance misuse at high rates often attributed to historical and contemporary traumas. In response, several Tribal Nations are addressing these issues through efforts to promote recovery and prevention to substance misuse. Study objectives were to partner with a Tribal Nation to develop a study to explore factors that contribute to the wellbeing of families to children with prenatal substance exposure and disseminate findings that can be translated back into the community. We applied Community-based participatory research (CBPR), strengths-based, and community-driven approaches during this two-year study development phase. We experienced challenges and identified solutions to partnering with one Tribal Nation on an epidemiological mixed-methods study centered on families with children that have prenatal substance exposure. Key inputs were becoming familiarizing with the community setting, structural supports for CBPR research, incorporating Indigenous CBPR principles, and developing a Community Advisory Team. We successfully collaborated with the Confederated Salish Kootenai Tribes Early Childhood Services program to develop a robust study design and a dissemination plan to ensure translation of study findings to the community. The robust study design consisted of common themes specific to a highly stigmatized study population, substance-abusing pregnant women, to protect participant confidentiality. Research alignment with community goals, allotting meaningful time to develop a research partnership, and incorporating culturally sensitive and community-relevant measures contributed to the successful development of an effective and rigorous study to better serve the Tribal Nation on addressing substance misuse.

DEcrease STress through RESilience training for Students (DESTRESS) Study: Protocol for a randomized controlled trial nested in a longitudinal observational cohort study.

INTRODUCTION: Chronic stress and burnout are highly prevalent among academically trained healthcare professionals, negatively affecting their well-being and capacity to engage in their work. Resilience to stress develops early in one's career path, hence offering resilience training to university students in these professions is one approach to fostering well-being and mental health. The aim of this study is to assess whether offering mindfulness-based resilience training to university students in healthcare professions reduces their perceived chronic stress. METHODS AND ANALYSIS: The study has a hybrid design combining a longitudinal observational cohort with a nested randomized controlled trial (RCT) with sequential multiple assignment and multistage adaptive interventions while taking participants' preferences into account. All students in healthcare related programmes at the Erasmus University Rotterdam are invited to participate. Within the observational cohort, students with a score of 14 or higher on the Perceived Stress Scale (PSS) are invited to take part in the RCT (n = 706). Eligible participants are randomized to control or active intervention in a ratio of 1:6. Those randomized to the control group and non-randomized participants in the cohort receive passive web-based psychoeducation about chronic stress and burnout through referral to specific websites. Participants randomized to the intervention group receive one of 8 active mindfulness-based interventions. They select a rank order of 4 preferred interventions and are randomized across these with equal probability. Non-response to the intervention is followed by sequential randomized assignment to another intervention, for a total maximum of 3 sequential interventions. All participants receive questionnaires at baseline, before and after each 8-week intervention period, and at 1- and 2-year follow-up. The primary outcome is perceived chronic stress measured with the PSS. Secondary outcomes include mental well-being, burnout, quality of life, healthcare utilization, drug use, bodyweight, mental and physical stress-related symptoms, resilience, and study progress. ETHICS AND REGISTRATION: Approval from the Medical Ethics Review Committee was obtained under protocol number MEC-2018-1645. The trial is registered in the Netherlands National Trial Register by registration number NL7623, 22/03/2019, https://www.trialregister.nl/.

Effect of Sugarcane Cultivar and Foliar Insecticide Treatment on Infestations of the Invasive Sugarcane Thrips, Fulmekiola serrata (Thysanoptera: Thripidae), in Florida.

Fulmekiola serrata (Kobus) was observed infesting sugarcane, Saccharum spp. hybrids, in the United States for the first time in January 2017 in Florida. Field studies were conducted to determine F. serrata infestation levels on popular sugarcane cultivars and to determine the efficacy of foliar insecticide treatments that could be used for management. Cultivar evaluations comparing six and five commercial cultivars representing >46% of the sugarcane production area in Florida were conducted in 2017 and 2018, respectively. Fulmekiola serrata infestation levels did not differ among cultivars in 2017. However, infestation levels on CP 00-1101 were greater than on CP 96-1252 grown on organic soils, and infestation levels on CP 96-1252 were greater than on CPCL 97-2730 grown on mineral soils in 2018. Three insecticide evaluations, two in 2017 and one in 2018, were conducted. The pyrethroid lambda-cyhalothrin, which is registered for use on sugarcane, was consistently associated with the greatest decreases in F. serrata infestation levels. The neonicotinoids imidacloprid and thiamethoxam, as well as the butenolide flupyradifurone, decreased infestation levels but to a lesser extent than did lambda-cyhalothrin. The spinosyn spinetoram was associated with the lowest decreases in F. serrata infestation levels. Our results supported short-term F. serrata management recommendations: Popular Florida sugarcane cultivars should be considered equally susceptible to F. serrata until additional evaluations are conducted and F. serrata outbreaks can be treated with lambda-cyhalothrin when infestations stress the crop beyond acceptable levels.

A convergent strategy towards febrifugine and related compounds.

We report a modular five step synthetic route to the febrifugines that employs 2-(chloromethyl)allyl-trimethylsilane as a conjunctive reagent for the coupling of the piperidine and quinazolinone groups. We also demonstrate the application of a recent Rh-catalyzed quinazolinone synthesis for the facile generation of febrifugine analogs.

Preclinical predictors that the orthosteric mGlu2/3 receptor antagonist LY3020371 will not engender ketamine-associated neurotoxic, motor, cognitive, subjective, or abuse-liability-related effects.

The novel mGlu2/3 receptor antagonist, LY3020371, has been shown to produce antidepressant-like effects comparable to that of the clinically-effective antidepressant ketamine. In the present study, we investigated whether LY3020371 would be predicted to be free of the side-effects and safety pharmacology issues associated with ketamine. In contrast to ketamine, LY3020371 produced small increases in locomotion and did not impair motor performance on an inverted screen. Ketamine, but not LY3020371, increased dopamine efflux in the nucleus accumbens of rats. Ketamine also produced cognitively-impairing effects in rats in a T-maze and in a psychomotor vigilance task and altered theta synchrony between the hippocampus and mPFC, whereas LY3020371 had either no significant impact or lesser effects in these assays. In mice, ketamine, but not LY3020371, negatively affected spontaneous alternation in a Y-maze. Rats were trained to discriminate LY3020371 from vehicle where 30mg/kg produced 100% drug-appropriate responding and the ED50 for LY3020371 was 9.4mg/kg, i.p. In rats discriminating LY3020371, neither d-amphetamine nor phencyclidine fully substituted for LY3020371 (35-45%) and the mGlu2/3 receptor agonist LY354740 partially attenuated the discriminative stimulus effects of LY3020371. These are the first data to demonstrate the discriminative stimulus effects of an mGlu2/3 receptor antagonist. Some alterations were suggested to occur in the density of mGlu2/3 receptor binding sites in the drug discrimination rats relative to their age-matched non-drug-exposed controls. In preclinical toxicology studies of 14day dosing of doses up to 1000mg/kg, i.v. in rats and up to 500m/kg, i.v. in Cynomologous monkeys, LY3020371 produced uM plasma exposures without producing critical toxicological findings. It is concluded that LY3020371 does not recapitulate the motor, cognitive, subjective, neurochemical, electrophysiological, or toxicological findings reported with ketamine. Thus, LY3020371 possesses both the efficacy signatures of a rapidly-acting antidepressant and a safety profile enabling proof of concept studies in patients.

Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

The ability of the N-methyl-d-aspartate receptor antagonist ketamine to alleviate symptoms in patients suffering from treatment-resistant depression (TRD) is well documented. In this paper, we directly compare in vivo biologic responses in rodents elicited by a recently discovered metabotropic glutamate (mGlu) 2/3 receptor antagonist 2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY3020371) with those produced by ketamine. Both LY3020371 and ketamine increased the number of spontaneously active dopamine cells in the ventral tegmental area of anesthetized rats, increased O2 in the anterior cingulate cortex, promoted wakefulness, enhanced the efflux of biogenic amines in the prefrontal cortex, and produced antidepressant-related behavioral effects in rodent models. The ability of LY3020371 to produce antidepressant-like effects in the forced-swim assay in rats was associated with cerebrospinal fluid (CSF) drug levels that matched concentrations required for functional antagonist activity in native rat brain tissue preparations. Metabolomic pathway analyses from analytes recovered from rat CSF and hippocampus demonstrated that both LY3020371 and ketamine activated common pathways involving GRIA2 and ADORA1. A diester analog of LY3020371 [bis(((isopropoxycarbonyl)oxy)-methyl) (1S,2R,3S,4S,5R,6R)-2-amino-3-(((3,4-difluorophenyl)thio)methyl)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (LY3027788)] was an effective oral prodrug; when given orally, it recapitulated effects of intravenous doses of LY3020371 in the forced-swim and wake-promotion assays, and augmented the antidepressant-like effects of fluoxetine or citalopram without altering plasma or brain levels of these compounds. The broad overlap of biologic responses produced by LY3020371 and ketamine supports the hypothesis that mGlu2/3 receptor blockade might be a novel therapeutic approach for the treatment of TRD patients. LY3020371 and LY3027788 represent molecules that are ready for clinical tests of this hypothesis.

Eating disorder behaviours amongst adolescents: investigating classification, persistence and prospective associations with adverse outcomes using latent class models.

Diagnostic criteria for eating disorders (ED) remain largely based on clinical presentations, but do not capture the full range of behaviours in the population. We aimed to derive an empirically based ED behaviour classification using behavioural and body mass index (BMI) indicators at three time-points in adolescence, and to validate classes investigating prospective associations with adverse outcomes. Adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) provided data on ED at age 14 (n = 6615), 16 (n = 5888), and 18 years (n = 5100), and had weight and height measured. Psychological and behavioural outcomes were assessed at 15.5/16 and 17.5/18 years. We fit gender- and age-stratified latent class models, and employed logistic regression to investigate associations between classes and later outcomes. One asymptomatic and two symptomatic (largely representing higher and lower frequency ED behaviours) classes were observed at each time-point, although their relative prevalence varied by age and gender. The majority of girls in symptomatic classes remained symptomatic at subsequent assessments. Girls in symptomatic classes had higher odds of subsequent anxiety and depressive disorders, binge drinking, drug use, and deliberate self-harm. Data analyses were underpowered amongst boys. The presence of two symptomatic classes (characterised by different ED behaviour frequency) and their prospective association with adverse outcomes suggest a need to refine diagnostic thresholds based on empirical data. Despite some instability of classes, particularly in mid-adolescence, evidence that half of girls in symptomatic classes remained symptomatic suggests persistence of ED behaviours in adolescence, and highlights a need for early identification to reduce chronicity.

Riparian proper functioning condition assessment to improve watershed management for water quality.

Pollutants can be reduced, ameliorated, or assimilated when riparian ecosystems have the vegetation, water, and soil/landform needed for riparian functions. Loss of physical form and ecological function unravels assimilation processes, increasing supply and transport of pollutants. Water quality and aquatic organisms are response measures of accumulated upstream discharges, and ultimately of changes in riparian functions. Thus, water quality monitoring often fails to identify or lags behind many causes of pollution or remediation from riparian degradation. This paper reviews the interagency riparian proper functioning condition (PFC) assessment for lotic (running water) riparian ecosystems and outlines connections between PFC and water quality attributes (sediment, nutrients, temperature, and dissolved oxygen [DO]). The PFC interaction of hydrology, vegetation, and soils/landforms influences water quality by dissipating energy associated with high waterflow, thereby reducing vertical instability and lateral erosion while developing floodplains with captured sediment and nutrients. Slowing flood water enables aquifer recharge, deposition, and plant nutrient uptake. Water-loving, densely rooted streambank stabilizing vegetation and/or wood helps integrate riparian functions to maintain channel pattern, profile, and dimension with characteristics for a diversity of habitats. A complex food web helps slow the nutrient spiral with uptake and storage. Temperature fluctuations are dampened by delayed discharges, narrower and deeper active channels, coarser substrates that enhance hyporheic interchange, and shade from riparian vegetation. After assessment and implementation, monitoring recovery of impaired riparian function attributes (e.g., streambank plant species) naturally focuses on persistent drivers of water quality and aquatic habitat. This provides timely environmental indicators of stream ecological health and water quality remediation projects or land management.

Rice root curling, a response to mechanosensing, is modulated by the rice E3-ubiquitin ligase HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENE1 (OsHOS1).

Plant development depends on the perception of external cues, such as light, gravity, touch, wind or nutrients, among others. Nevertheless, little is known regarding signal transduction pathways integrating these stimuli. Recently, we have reported the involvement of a rice E3-ubiquitin ligase (OsHOS1, HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENE1), previously associated with abiotic stress response, in root responses to mechanical stimuli. We showed that OsHOS1 is involved in the regulation of root curling after mechanosensing and that RNAi::OsHOS1 plants failed to exhibit the root curling phenotype observed in WT. Interestingly, the straight root phenotype of these transgenics correlated with the up-regulation of rice ROOT MEANDER CURLING (OsRMC, a negative regulator of rice root curling) and was reverted by the exogenous application of jasmonic acid. Altogether, our results highlight the role of the proteasome modulating plant responses to mechanical stimuli and suggest that OsHOS1 is a hub integrating environmental and hormonal signaling into plant growth and development.

Are We Missing Something Pertinent? A Bias Analysis of Unmeasured Confounding in the Firearm-Suicide Literature.

Despite the magnitude and consistency of risk estimates in the peer-reviewed literature linking firearm availability and suicide, inferring causality has been questioned on the theoretical basis that existing studies may have failed to account for the possibility that members of households with firearms differ from members of households without firearms in important ways related to suicide risk. The current bias analysis directly addresses this concern by describing the salient characteristics that such an unmeasured confounder would need to possess in order to yield the associations between firearm availability and suicide observed in the literature when, in fact, the causal effect is null. Four US studies, published between 1992 and 2003, met our eligibility criteria. We find that any such unmeasured confounder would need to possess an untenable combination of characteristics, such as being not only 1) as potent a suicide risk factor as the psychiatric disorders most tightly linked to suicide (e.g., major depressive and substance use disorders) but also 2) an order of magnitude more imbalanced across households with versus without firearms than is any known risk factor. No such confounder has been found or even suggested. The current study strongly suggests that unmeasured confounding alone is unlikely to explain the association between firearms and suicide.

Protein concentration and mitochondrial content in the gastrocnemius predicts mortality rates in patients with peripheral arterial disease.

OBJECTIVE: This study evaluated the hypothesis that protein concentration and mitochondrial content in gastrocnemius biopsies from patients with peripheral arterial disease (PAD) predict mortality rates. BACKGROUND: PAD patients experience advancing myopathy characterized by mitochondrial dysfunction, myofiber degradation, and fibrosis in their ischemic legs, along with increased mortality rates. METHODS: Samples from the gastrocnemius of PAD patients were used for all analyses. Protein concentration was normalized to muscle wet weight, and citrate synthase activity (standard measure of mitochondrial content in cells) was normalized to muscle wet weight and protein concentration. Protein and citrate synthase data were grouped into tertiles and 5-year, all-cause mortality for each tertile was determined with Kaplan-Meier curves and compared by the modified Peto-Peto test. A Cox-regression model for each variable controlled for the effects of clinical characteristics. RESULTS: Of the 187 study participants, 46 died during a mean follow-up of 23.0 months. Five-year mortality rate was highest for patients in the lowest tertile of protein concentration. Mortality was lowest for patients in the middle tertile of citrate synthase activity when normalized to either muscle wet weight or protein concentration. The mortality hazard ratios (HRs) from the Cox analysis were statistically significant for protein concentration normalized to muscle wet weight (lowest vs middle tertile; HR = 2.93; P = 0.008) and citrate synthase normalized to protein concentration (lowest vs middle tertile; HR = 4.68; P = 0.003; and lowest vs highest tertile; HR = 2.36; P = 0.027). CONCLUSIONS: Survival analysis of a contemporaneous population of PAD patients identifies protein and mitochondrial content of their gastrocnemius as predictors of mortality rate.

The structured diagnostic interview for sleep patterns and disorders: rationale and initial evaluation.

OBJECTIVES: We aimed to describe and report the initial validity of a newly developed structured interview for sleep disorders (Diagnostic Interview for Sleep Patterns and Disorders [DISP]) administered by trained lay interviewers. METHODS: A total of 225 patients with various sleep disorders were recruited from two nationally recognized sleep centers in the United States. The International Classification of Sleep Disorders, second edition (ICSD-2) criteria, were used to classify sleep disorders (e.g., delayed sleep phase disorder, hypersomnia, narcolepsy with cataplexy [NC], restless legs syndrome [RLS], periodic limb movement disorder [PLMD], insomnia, rapid eye movement sleep behavior disorder [RBD], and obstructive sleep apnea [OSA]). Interview diagnoses were compared with final diagnoses by sleep specialists (reference diagnosis based on clinical history, examination, and polysomnography [PSG] when indicated). RESULTS: DISP diagnoses had fair to substantial concordance with clinician diagnoses for various sleep disorders, with area under the receiver operator characteristic curves (AUC) ranging from 0.65 to 0.84. Participants classified by the clinician as having a sleep disorder were moderately well-detected (sensitivity ranging from 0.50 for RBD disorder to 0.87 for insomnia). Substantial specificity (>0.8) also was seen for five of the eight sleep disorders (i.e., delayed sleep phase, hypersomnia, NC, PLMD, and RBD). Interviews were more likely than clinicians to detect disorders secondary to the primary sleep problem. CONCLUSIONS: The DISP provides an important tool for the detection of a wide range of sleep disorders in clinical settings and is particularly valuable in the detection of secondary disorders that were not the primary referral diagnosis.

Assessment and reporting of the clinical immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical recommendations.

Immunogenicity is a significant concern for biologic drugs as it can affect both safety and efficacy. To date, the descriptions of product immunogenicity have varied not only due to different degrees of understanding of product immunogenicity at the time of licensing but also due to an evolving lexicon that has generated some confusion in the field. In recent years, there has been growing consensus regarding the data needed to assess product immunogenicity. Harmonization of the strategy for the elucidation of product immunogenicity by drug developers, as well as the use of defined common terminology, can benefit medical practitioners, health regulatory agencies, and ultimately the patients. Clearly, understanding the incidence, kinetics and magnitude of anti-drug antibody (ADA), its neutralizing ability, cross-reactivity with endogenous molecules or other marketed biologic drugs, and related clinical impact may enhance clinical management of patients treated with biologic drugs. To that end, the authors present terms and definitions for describing and analyzing clinical immunogenicity data and suggest approaches to data presentation, emphasizing associations of ADA development with pharmacokinetics, efficacy, and safety that are necessary to assess the clinical relevance of immunogenicity.

Should we continue to drain the pylorus in patients undergoing an esophagectomy?

A systematic review of the literature was performed to assess the necessity of a pyloric drainage procedure during an esophagectomy with gastric conduit reconstruction. Earlier data recommend performing a pyloric drainage procedure for all esophagectomies; however, recent studies have questioned this. A thorough literature search (January 2001-November 2011) was performed using the terms esophagectomy, pyloroplasty, pyloromyotomy, botulinum toxin, and pyloric drainage. Only studies that compared patient outcome after undergoing an esophagectomy with a pyloric drainage procedure with those undergoing an esophagectomy without a pyloric drainage procedure were selected. Only four studies, comprising 668 patients in total, were identified that compared patient outcome after undergoing an esophagectomy with or without a pyloric drainage procedure, and two additional meta-analyses were identified and selected for discussion. All studies were retrospective, and because of the heterogeneity of studies, patient demographics, reporting, and statistical analysis of patient outcome, pooling of data and meta-analysis could not be performed. Careful analysis demonstrated that pyloric drainage procedure was associated with a non-significant trend for delayed gastric emptying and biliary reflux, while not affecting the incidence of dumping. No correlation was determined between a pyloric drainage procedure and anastomotic leaks, postoperative pulmonary complications, length of hospital stay, and overall perioperative morbidity. While there are risks associated with a pyloric drainage procedure and data exist supporting its omission during an esophagectomy, no good conclusion can be drawn from the current literature. Larger multi-institutional, prospective studies are required to definitively answer this question.

Childhood maltreatment, juvenile disorders and adult post-traumatic stress disorder: a prospective investigation.

BACKGROUND: We examine prospectively the influence of two separate but potentially inter-related factors in the etiology of post-traumatic stress disorder (PTSD): childhood maltreatment as conferring a susceptibility to the PTSD response to adult trauma and juvenile disorders as precursors of adult PTSD. METHOD: The Dunedin Multidisciplinary Health and Development Study (DMHDS) is a birth cohort (n = 1037) from the general population of New Zealand's South Island, with multiple assessments up to age 38 years. DSM-IV PTSD was assessed among participants exposed to trauma at ages 26-38. Complete data were available on 928 participants. RESULTS: Severe maltreatment in the first decade of life, experienced by 8.5% of the sample, was associated significantly with the risk of PTSD among those exposed to adult trauma [odds ratio (OR) 2.64, 95% confidence interval (CI) 1.16-6.01], compared to no maltreatment. Moderate maltreatment, experienced by 27.2%, was not associated significantly with that risk (OR 1.55, 95% CI 0.85-2.85). However, the two estimates did not differ significantly from one another. Juvenile disorders (ages 11-15), experienced by 35% of the sample, independent of childhood maltreatment, were associated significantly with the risk of PTSD response to adult trauma (OR 2.35, 95% CI 1.32-4.18). CONCLUSIONS: Severe maltreatment is associated with risk of PTSD response to adult trauma, compared to no maltreatment, and juvenile disorders, independent of earlier maltreatment, are associated with that risk. The role of moderate maltreatment remains unresolved. Larger longitudinal studies are needed to assess the impact of moderate maltreatment, experienced by the majority of adult trauma victims with a history of maltreatment.